Interleukin-8 (IL-8, neutrophil activating protein-1, or NAP-1) is a member of C-X-C chemokine family of related cytokines having broad involvement in inflammatory responses, tissue injury, growth regulation and cellular adhesion. Cerretti, D. P., et al., Molecular Characterization of Receptors for Human Interleukin-8, GRO/Melanoma Growth-Stimulatory Activity and Neutrophil Activating Peptide-2, Molecular Immunology, 30(4), 359-367 (1993); and Koch, A. E., et al., In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis, Pathobiology, 61(5-6), 239-46 (1993). A review of the C-X-C family is given in Streiker, R. M., et al., Role of C-X-C Chemokines As Regulators Of Angiogenesis In Lung Cancer, J. of Leukocyte Biology, 57, 752-762 (1995). IL-8 has also been shown to have a potent stimulatory effect on angiogenesis. See, e.g., Koch, A. E., Interleukin-8 as a Macrophage-Derived Mediator of Angiogenesis, Science, 258, 1798-1800 (1992).
It is known that IL-8 is produced by a variety of normal human somatic cells including monocytes/macrophages, dermal fibroblasts, vascular endothelial cells, keratinocytes, and mesangeal cells. Yasumoto, K., et al., Tumor Necrosis Factor Alpha and Interferon Gamma Synergistically Induce Interleukin 8 Production in a Human Gastric Cancer Cell Line Though Acting Concurrently on AP-1 and NF-kB-like Binding Sites of the Interleukin 8 Gene, J. of Biological Chemistry, 267(31), 22506-11 (1992). Apparently, such cells produce IL-8 only when stressed, and not under conditions of normal growth and homeostasis,. Factors which induce IL-8 production include inflammation, IL-1, TNF, LPS and thrombin.
It is also known that Il-8 is commonly secreted by tumor cells. Tumor is herein defined to mean uncontrolled and progressive multiplication of cells, including benign tumors and all forms of neoplasm and cancer. In one study IL-8 was shown to be present in 80% of carcinoma cell lines and 83.3% of cancer tissues studied. It has also been shown that IL-8 is a growth factor for cancers, and that anti-IL-8 antibody and IL-8 receptor anti-sense are each be effective in attenuating cancer cell growth in vitro. Ishoko, T., et al, Supra; Schadendorf, D., et al., IL-8 Produced by Human Malignant Melanoma Cells in Vitro Is an Essential Autocrine Growth Factor, J. Immunol., 151(5), 2667-2674 (1993).
Because of its effects on growth, it is suspected that IL-8 has a significant role in the metastatic spread of melanoma and other cancers. Schadendorf, D., et al., Supra. It has been demonstrated, for example, that IL-8 is directly involved in the mechanism of melanoma metastasis, (Singh, R. K., et al, Ultraviolet B Irradiation Promotes Tumorigenic and Metastatic Properties in Primary Cutaneous Melanoma via Induction of Interleukin 8, Cancer Res., 55, 3669-3674, 1995), as well as lung cancer, (Greenspoon, S. A., et al., The expression of IL-8 during Tumorgenesis and Metastasis in a model of human nonsmall cell lung cancer/SCID mouse chimera, Clinical Research, 42, 404A, 1994). IL-8 has also been found to play role in tumor neovascularization, for example, in head and neck squamous cell carcinomas. Cohen R. F., et al, Arch Otolaryngol. Head Neck Surg., 121, 202-209, 1995. Thus, IL-8 plays important role in tumor growth, metastasis and angiogenesis.